Nonalcoholic fatty liver (NAFL) includes a wide spectrum of processes, including hepatic steatosis and nonalcoholic steatohepatitis (NASH), which can progress to end-stage liver disease in 20%-40% of patients with NASH. We are proposing to compare the Magnetic Resonance Spectroscopy (MRS) spectra patterns of patients with NASH to the degree of fibrosis on liver histology stages 1 through 4 (Kleiner, et al), and a control group with simple steatosis. Our goal is to demonstrate increased PME/PDE ratios with increasing fibrosis. Demonstration of such a difference will lead to the development of noninvasive methods of evaluating longitudinal progression, or regression, of NASH in its natural history, as well as providing a means to follow up on the response to therapeutic interventions. Successful identification of unique MRS spectra may prove to be a potential modality for future investigation into the pathophysiology of NASH and the role of MRS as a noninvasive surrogate to liver biopsy in understanding mitochondrial abnormalities, including respiratory chain defects. MRS spectra from different stages of fibrosis in subjects with NASH will be analyzed by determining peak areas from PME, Pi, PDE, and NTP via a standard MRS signal quantitation algorithm (Advanced Magnetic Resonance algorithm) and compare them to the control group of simple steatosis, as well as to each group of NASH patients separately. Peak area ratios (PME/NTP, PDE/NTP, PME/PDE, and Pi/NTP) will be calculated, and statistically analyzed. The study design permits adequate statistical assessment upon examination of eighty-six patients. This award will provide me with the necessary tools to further expand my expertise in the field of fatty liver disease, with an emphasis on research in NASH/NAFL and the noninvasive techniques of assessment of disease severity and responsiveness to different therapeutic modalities. I also anticipate the facilitation of future grant funds from NIH and other funding agencies, to conduct MR Spectroscopy in NAFL patients and correlate the MR spectra to biochemical markers of fibrosis. We would also be able to use this tool in conjunction with liver biopsy in patients undergoing therapeutic management of NAFLD, i.e., Insulin sensitizers, anti-oxidant, and other studied therapies in patients with nonalcoholic fatty liver disease. PUBLIC HEALTH RELEVANCE: Fatty liver disease that is not the result of alcohol intake is an increasing and unmet need in the US and worldwide. Currently, the only method available to study disease progression and the effectiveness of interventions is through invasive liver biopsies, which inconvenience the patient, and are subject to complications and sampling error. We are proposing to explore whether a non-invasive imaging technique (magnetic resonance spectroscopy) can be used to provide a more accurate and informative method to study these patients.